Aspirin in Pregnancy: Maternal and Fetal Effects

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Aspirin

in Pregnancy:

Maternal

and Fetal

Effects

Donald G. Corby, M.D.

From the Clinical Investigation Service, Fitz.cimons Army Medical Center, Denver

ABSTRACT. Recent surveys of prenatal drug consumption indicate that aspirin is the most frequently consumed drug in

pregnancy. Over the past several years, numerous reports

have suggested a possible association between prenatal aspirin ingestion and adverse effects in the pregnant woman and her developing fetus. This review summarizes the available experimental animal and human epidemiological

data on the possible teratogenicity of aspirin, its effects on fetal lethality, its effects on the duration of pregnancy and parturition, and its ability to alter hemostatic mechanisms in both the mother and newborn. From an analysis of the data, it appears that, although direct conclusive evidence of adverse effects in humans is lacking, a potential hazard does

exist and thus “the indiscriminate use of aspirin during

pregnancy is contraindicated.” Pediatrics 62(stippl):930-937,

1978, aspirin, teratogenicity, fetal lethality, hemostasis.

To take medicine is, perhaps, the greatest feature that

distinguishes man from animals. SIR WILLIAM O5LER

Recent surveys of prenatal drug consumption

indicate that aspirin is the most frequently

consumed drug in pregnancy. This is not

surpris-ing in view of its availability as an “over the

counter” medication. The extent of its usage is,

however, not only unexpected but alarming. In

1964, Carter1 estimated that more than one half

of all women ingest aspirin during pregnancy.

Hill2 interviewed 156 gravid women who were

delivered of infants at a private hospital in

Houston from 1969 to 1971. She discovered that

64% of these women took salicylates during

pregnancy. Forfar and Nelson3 surveyed 911

randomly selected pregnant Scottish women, and

found that 54% had taken salicylates. Of more

significance, however, they calculated, using a

“drug consumption in pregnancy” factor, that

two thirds took aspirin in doses equivalent to full

conventional dosage for at least six weeks of the

pregnancy. Collins and Turner4 found, in addition

to the usual high percentage of women who

intermittently took aspirin, that 6.6% of all

women attending the prenatal clinics at Women’s

Hospital, Sydney, Australia, were “habituated” to

powders containing aspirin, phenacetin or

salicyl-amide, and caffeine.

Over the past several years, numerous reports

have indicated a possible association between

prenatal aspirin ingestion and adverse effects in

the pregnant female and the developing fetus.

Most of these studies used experimental animals.

Because moral and ethical considerations

pre-dude randomized investigations that could

prospectively examine the effects of aspirin in

human pregnancies, several investigators have

carried out epidemiological studies. Most have

focused on the following aspects: teratogenic

effects, the incidence of stillbirths and neonatal

deaths, the effects of aspirin on the duration and

course of pregnancy and parturition, and the

ability of aspirin to impair the hemostatic

mech-anisms of the mother or newborn infant. A small

number of animal investigations also suggest that

aspirin taken prenatally may have long-term

consequences on the infant. It is the intent of this

review to bring together the available

informa-tion on these subjects so that the reader might

decide the possible risks of aspirin consumption

during pregnancy.

First, it seems appropriate to briefly review the

pharmacokinetic processes that determine the

extent of fetal exposure to aspirin consumed by

the mother during pregnancy. The factors

involved are the rate of intake of drug by the

mother, the kinetics of drug transfer between the

Read before the Aspirin and Acetaminophen Symposium,

New York, November 4-5, 1977.

The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

ADDRESS FOR REPRINTS: (DCC.) Clinical Investigation Service, Fitzsimons Army Medical Center, Denver, CO 80240.

at Viet Nam:AAP Sponsored on September 7, 2020

www.aappublications.org/news

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mother and fetus, the rate of elimination of drug

by the mother and fetus, and the transfer of drug

from mother to nursing infant through breast

milk.

Salicylate is readily transferred from mother to

fetus across the placenta. Palmisano and Gassady5

examined umbilical cord sera from 272

consecu-tively delivered infants and found salicylate levels

in excess of 1 mg/dl in 9.5%; the mean

concentra-tion was 3.3 mg/dl, with a range of 1.2 to 10.9

mg/dl. The infant eliminates salicyluric acid and

other metabolites of salicylate more slowly than

adults because of the immaturity of the

glucuron-idation and renal excretory pathways. This results

in a higher concentration of drug in the fetus and

increases the length of exposure to the drug. In

addition, the volume of distribution of salicylate is

larger in the newborn or fetus near term (300 to

350 mg/kg of body weight) than in older children

and adults (approximately 200 mg/kg).” Thus, a

given plasma concentration of salicylate in the

newborn or fetus reflects a larger amount of drug

per unit of body weight than does the same

concentration in older children and adults.

Aspirin is readily transferred to the infant by

the nursing mother. However, when aspirin is

taken in therapeutic dosage, it passes into the

breast milk in amounts that are undetectable or so

low as to be nontoxic. The effects of toxic doses of

aspirin are not known, but conceivably they could

be adverse in the infant. For a further discussion

of the pharmacokinetics of aspirin in the neonate,

the reader is referred to the excellent recent

review by Levy.7

TERATOGENIC EFFECTS

Animal Studies

The teratogenic properties of salicylate were

first demonstrated by Warkany and Takacs.5

They found that congenital malformations could

be induced in rats by administering methyl or

sodium salicylate

in

high doses to pregnant

females from days 9 to 1 1 of gestation. The most

frequent anomaly was craniorrhachischisis. This

was particularly important because, although it is

extremely rare in humans, its origin is closely

related to anencephaly, exencephaly, and spina

bifida. Less frequently observed malformations

were exencephaly, facial clefts, eye defects,

gastroschisis, and irregularities of the vertebrae

and ribs. Larsson and Eriksson” were also able to

induce similar abnormalities in A/Jax strains of

newborn mice when pregnant females were

treated with sodium salicylate early in gestation.

Trasler’#{176} induced cleft lips in the offspring of

pregnant A/Jax mice by administering aspirin

(500 mg/kg) over a 24-hour period between the

eighth and tenth days of gestation. Additional

evidence of the teratogenic properties of aspirin

was provided by Palmer,” who demonstrated

significant changes in the rib patterns of newborn

CD rats whose mothers were treated with

aspi-rin.

Studies by Wilson’2 disclosed that doses of

aspirin five to six times higher than those used in

rodents produced embryotoxicity and similar

malformations in rhesus monkeys.

The terratogenic effects of aspirin in

experi-mental animals also appear to be influenced by

the concomitant administration of other drugs.

Salicylates potentiate the effect of cortisone in

inducing cleft palate forination in rodents.’ Levy

et al.’4 showed that the teratogenic effect of

aspirin can be appreciably enhanced by the

concurrent administration of benzoic acid, a

widely used food preservative.

Other environmental factors also alter the

tera-togenicity of aspirin. l3eall and Klein’5 reported

that food restriction during aspirin

administra-tion greatly increased the forlnation of congenital

malformations in rats (96%) when compared with

normally fed controls (24%). Maternal stress also

has been shown to increase the rate of

malforma-tions in animals.”

The results of these animal experiments can

obviously not be directly extrapolated to man. In

all studies, there was considerable interspecies

and individual variation, and the doses of

salicy-late used to induce teratogenesis were excessively

high when compared to those normally used in

man. Nevertheless, because many of the

uncon-trollable confounding factors of epidemiological

studies can be eliminated, these animal studies are

valuable in evaluating similar associations found

in some of the epidemiological studies discussed

in the following paragraphs.

Human Studies

Richards,’7 in a retrospective study of 833

consecutive cases from the South Wales Survey of

Congenital Defects, found that, when compared

with matched controls (women matched for age,

parity, social class, area of residence, and date of

delivery who had given birth to normal infants),

significantly more mothers with malformed

infants had ingested salicylates during pregnancy

(22.3% vs 14.4%; P < .01). With the exception of

the cardiovascular system, there was, in relation

to each affected system, a higher proportion of

aspirin users than controls. Striking differences

in rates were also seen when the individual

defects were examined; however, talipes was the

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TABLE I

MATERNAL DRuc CONSUMPTION AND ORAL CLEFTS#{176}

% of Entire % of Cases With % of Gases

Study Group

A___

No Additional Defects With Additional

Defects

r-

-Subjects Controls (Pt CL (P)f -- 0

(N = 599) (N = .5.90) A Subjects Controls

(N = 134) (N = 1.32)

,----Subjects Controls Subjects Controls

(N = 2.32) (N = 226) (N = 232) (N = 230)

Salicylates

1st trimester 14.9 5.6 10.3 5.8 19.8 5.2 14.3 6.1

2nd trimester 11.5 6.6 10.3 6.2 10.3 4.8 15.7 10.6

3rd trimester 8.0k 4.6 7.8 2.7 10.3 5.2 4.5 6.1

Time of intake 18.4 16.9 19.8 19.9 16.4 17.8 19.4 10.6

not reported

#{176}FromSaxen.”

tCP indicates cleft palate; CL (P), cleft lip with or without cleft palate.

:1:1’ < .001

(x2).

§P < .05 (2)

lip < .01

(x2).

only defect in which the difference reached an

acceptable level of significance. The taking of

aspirin was significantly more frequent in cases

than in controls whether or not there was a

history of cough or colds. A similar pattern was

also seen for other febrile illnesses, suggesting that

it was the aspirin that was teratogenic rather than

the conditions for which it was taken.

Neverthe-less, the author concluded that either the results

of his studies “suggest that salicylates have a

teratogenic effect or that the conditions for which

they were taken have such an action.”

In a similar type of retrospective study, Nelson

and Forfar’8 found that aspirin had been taken by

a higher proportion of mothers of infants with

congenital malformations than controls (62.2% vs

54.3%; P < .01).

Saxen’4 studied 599 oral cleft cases reported to

the Finnish Register of Congenital Malformations

from 1967 to 1971. He found the consumption of

aspirin during the first trimester was nearly three

times as frequent in mothers of infants with clefts

as in control mothers. The rate (19.8%) was

highest for infants with both cleft lip and

palate-nearly four times that of the

correspond-ing control group (Table I).

Turner and Collins2#{176} found major congenital

abnormalities in six of 144 infants of mothers who

regularly took salicylates during pregnancy. This

rate not significantly different from that found in

all infants delivered at that hospital during the

two-year study period (4.2% vs 2.4%).

Interesting-ly, however, there was a higher incidence of

malformations in infants of the mothers who

intermittently took salicylates (more than once

per week) than in those who took them several

times a day. This observation suggests that any

teratogenic effect may be more related to

fluc-tuating drug levels than to constantly elevated

levels during the first trimester.

Crombie et al.2 ‘ compared the number of

aspirin prescriptions issued by English physicians

to women in early pregnancy who eventually

were delivered of congenitally malformed infants

with the number of aspirin prescriptions issued to

women who were delivered of normal infants.

There was no statistically significant difference

between the two sets of mothers. The authors

concluded that any relationship between “drug

consumption and a congenital abnormality is

indirect and possibly more related to the morbid

conditions for which the drugs were given.”

A recent prospective study by Slone et al.,22

conducted in 12 hospitals throughout the United

States, evaluated aspirin usage and the incidence

of congenital malformations in a cohort of more

than 50,000 mother-child pairs. They divided

these patients into three groups as follows: heavy

aspirin users (aspirin at least eight times in any of

the first four months of pregnancy), occasional

aspirin users, and controls (no history of aspirin

ingestion). After controlling for potential

con-founding factors using multivariate analysis, the

overall malformation rates were similar in 5,128

heavily exposed children, 9,736 other exposed

children, and 35,418 children who were not

exposed to aspirin during the first four lunar

months of pregnancy (Table II). When the infants

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TABLE II

CONGENITAL MALFORMATIONS FOLLOWING ASPIRIN

EXPOSURE IN EARLY PREGNANCY#{176}

TABLE III

with congenital malformations were further

divided by outcome, i.e., uniform malformations

(

CNS, cardiovascular, etc.) and nonuniform

malformations (inguinal hernia and clubfoot), the

data showed that both aspirin-exposed groups

were similar to the unexposed group. The authors

concluded that the study gave no evidence that

aspirin ingestion in conventional doses during

pregnancy is associated with congenital

malfor-mations. They did not discount, however, the

possibility that grossly excessive exposure to

aspirin may be teratogenic. The conclusion of the

authors is not surprising because they were really

studying three nonabusing populations and the

outcome could be easily predicted.

In all of these studies, the possible teratogenic

effects of aspirin were based on statistical

comparisons; observed differences could

there-fore have occurred by chance. Conversely, true

associations could be missed. In some studies, the

number of patients was too small to show

signifi-cant differences. Nevertheless, the fact that there

was no evidence incriminating aspirin does not

necessarily exonerate it from possible teratogenic

effects. On the other hand, the consumption of

aspirin by a higher proportion of mothers giving

birth to malformed infants as compared to

moth-ers with normal infants does not necessarily mean

that the drug has a teratogenic effect. There could

be several explanations. First, if a disease were

responsible for the development of congenital

abnormalities, aspirin taken to alleviate the

symp-toms of that disease might appear to be

terato-Group

It

Group

Ill:

Group

III

No. of malformed 343 663 2,242

children

% of group 6.7 6.8 6.3

Relative risk 1.06 1.08 1.0

#{176}FromSlone et

tContaining 5,128 “heavily” aspirin-exposed mother-child

pairs.

Containing 9,736 aspirin-exposed mother-child pairs.

§Containing 35,418 nonaspirin-exposed mother-child pairs.

genic. Second, symptoms produced in the mother

by a congenitally abnormal fetus might result in a

significant association between the aspirin used

for treatment of these symptoms and the

congen-ital abnormality. Third, in the early weeks of

pregnancy, the incidence of certain severe

malformations in the embryo may be higher than

that seen in stillborn or liveborn infants. Most of

these abnormal embryos are aborted; however, if

aspirin inhibits spontaneous abortion of an

al-ready malformed fetus, it would appear to be

responsible for disturbing organogenesis. Finally,

where a drug is used in combination, a

teratogen-ic effect of one drug might appear also to be

present in the other.

INCIDENCE OF MAIN CLINICAL FEATURES FROM REGULAR SALICYLATE INGESTION DURING

0

Group It Group II Controls

Anemia in pregnancy (%) 4111 2211 2011

Antepartum hemorrhage (%) 14 7 4

Postpartum hemorrhage (%) 12 7 2

Transfusion at delivery (%) 12 6 0

Mean duration of pregnancy (wk) 39.7 39.8 38.7

Duration 36 weeks or less (%) 5.0 5.0 8.0

Duration 42 weeks or more (%) 16.0 16.0 4.0

Mean duration of labor (hr) 5.6 5.5 4.8

Complicated delivery 30 27 11

Cesarean section 12 6 2

Stillbirths 4/57 1/81 0

Major congenital anomalies 2/64 4/82 1/64

#{176}FromTurner and Collins.2”

tGonstant takers: analgesics taken 2 to 12 times daily during entire pregnancy.

::Intermittent takers: analgesics taken at least once weekly during entire pregnancy. §Controls: no analgesics taken during entire pregnancy.

lip < .025.

#{182}P < .050.

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TABLE IV

STILLBIRTHS, NEONATAL DEATHS, AND MEAN BIRTH WEIGHTS FOLLOWING ASPIRIN EXPOSURE

DURING PREGNANCY#{176}

Group It Group II:t: Group III

No. of stillbirths 21 296 203

%ofgroup 1.4 1.2 1.4

No. of neonatal deaths 17 252 168

% of group 1.7 1.0 1.1

Mean birth weight (gm) (standardized [± SEM])

White 3,223( ± 20.4) 3,268( ± 4.6) 3,269( ± 6.1)

Black 3,074( ± 17.0) 3,047( ± 4.6) 3,046( ± 6.2)

#{176}FromShapiro et al.27

tContaining 1,515 heavily aspirin-exposed mother-child pairs. lContaining 24,866 intermediate aspirin-exposed mother-child pairs. §Containing 14,956 nonaspirin-exposed mother-child pairs.

FETAL LETHALITY

Teratogenicity and fetal lethality are most

likely different degrees of the same reaction of the

embryo to injury. Generally, lethal effects are

most pronounced at the time of implantation. The

studies of Larsson and Eriksson2’ are particularly

important because they showed that the rate of

resorptiOn of fetal A/Jax mice increased progres.

sively as sodium salicylate was administered to

the pregnant females on days 9, 11, 13, 15, and 17.

Other investigators have also reported an

increased rate of stillbirths with the oral

adminis-tration of aspirin-like drugs during the last two or

three days of rat pregnancies.2426

Collins and Turner4 found significantly

de-creased birth weights, increased fetal wastage,

and increased perinatal mortality in infants of

mothers who chronically ingested salicylates

throughout pregnancy (Table III). These findings

led them to conclude that the regular

consump-tion of aspirin by these patients was detrimental

to the welfare of their babies.

On the other hand, Shapiro et al.,27 using the

collaborative perinatal project previously

de-TABLE V

scribed by Slone et al.,22 could find no evidence

that prenatal aspirin is a cause of stillbirths,

neonatal deaths, or reduced birth weight (Table

IV).

EFFECTS ON PREGNANCY AND

PARTURITION

Recently, it has been shown that at least one

mechanism of the action of aspirin is related to

inhibition of prostaglandin synthesis.25 One of the

known actions of prostaglandins is to initiate

uterine contractions. Thus, one might anticipate

that aspirin would delay the onset and increase

the length of labor.

Tuchmann-Duplessis et al.27 showed that

ad-ministration of aspirin (200 mg/kg/day) to rats

during the last six days of gestation caused

prolon-gation of duration of pregnancy, prolongation of

parturition time, and appearance of dystocia in

some animals, resulting in possible death of

fetuses in utero. Aiken,24 Chester et al.,25 and

Waltman et al.26 also reported prolonged

gesta-tion in rats administered aspirin in the last two

days of pregnancies.

Lewis and Schulman” reported a 20-year

INFLUENCE OF ASPIRIN ON DURATION OF HUMAN GESTATION AND LABOR#{176}

Group It Group Ill: Group III

Length of gestation (days) 286.1 ± 13.3 275.2 ± 10.6 278.6 ± 6.91 Length of labor (hr) 12.1 ± 10.6 7.3 ± 4.11 6.96 ± 4.96 Birth weight (gm) 3,077.0 ± 597.0 2,972.0 ± 538.0 3,379.0 ± 460.0 Estimated blood loss (ml) 340.0 ± 155.0 244.0 ± 1 14.0 235.0 ± 97.0

#{176}FromLewis and Schulman.”

tPatients with rheumatic diseases taking therapeutic dosages of aspirin with daily consumption greater than 3,250 mg for at least the last six months of gestation (103 patients).

lControl patients with rheumatic diseases not taking aspirin (52 patients). §Gontrol healthy women not taking aspirin (50 women).

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retrospective study of 103 patients with

rheumat-ic diseases who had taken doses of aspirin greater

than 3,250 mg/day during the last six months of

their pregnancies. These women were compared

with two separate control groups: pregnant

women with rheumatic diseases who did not take

aspirin, and pregnant women without evidence of

rheumatic disease who also did not take aspirin.

The authors found that aspirin administration was

associated with a highly significant increase in

average length of gestation, an increase in

frequency of postmaturity, and an increase in

mean duration of spontaneous labor (Table V).

Collins and Turner,4 in their study of Australian

women who chronically had taken large doses of

salicylates throughout pregnancy, also found

prolonged gestation and an increase in

compli-cated deliveries (Table II).

EFFECTS ON HEMOSTASIS

Aspirin has been known for some time to

adversely affect platelet function. It does so l)y

blocking the action of cyclooxygenase, an enzyme

necessarY for the conversion of platelet-bound

( arachidonic acid tp prostaglandin interpediates

(endoperoxides and thromboxane), ?hih play an

important role in the regulation of platelet

func-tion. Thus, it is not surprising that prenatal

aspirin has been reported to be associated with

increased incidence of hemorrhage in both the

pregnant woman and the newborn infant.

Interference With Maternal Hemostatic

Mechanisms

In the study of Lewis and Schulman,’#{176} the

average blood loss at delivery in patients with

histories of heavy aspirin ingestion in the last six

months of pregnancy was significantly increased

as compared to the two control groups (P < .025)

(Table V). Collins and Turner4 also found that the

incidence of antepartum and postpartum

hemor-rhage as well as the need for transfusions at

delivery was significantly increased in the

moth-ers who chronically ingested large amounts of

salicylates (Table V).

Effect on Neonatal Hemostasis

Several years ago, Corby and Schulman3’

suggested that aspirin taken just prior

to

delivery

might cause a decrease in platelet function in the

newborn infant. In vitro studies of dose response

showed that the newborn’s platelets were much

more sensitive to aspirithan were those of the

mother. ‘

There have been several case reports3233 of

minor bleeding tendencies (purpura, petechiae,

and cephalohematoma) in infants whose mothers

had ingested aspirin prior to delivery. However,

with the exception of the patient of Haslam et

al.,’4 who had a gastrointestinal hemorrhage

requiring transfusion, there have been no reports

of serious or fatal hemorrhages in infants of

mothers who had ingested aspirin. Therefore,

although an association had definitely been shown

between maternal aspirin ingestion and a

poten-tial hemorrhagic tendency in the newborn infant,

the significance of this finding in normal full-term

newborns is unclear. Aspirin-induced platelet

dysfunction may, however, have clinical

rele-vance during difficult traumatic deliveries or in

the presence of other hemostatic defects.

Prelim-mary studies of premature infants whose mothers

have ingested aspirin during the week prior to

delivery suggest that this drug might be a risk to

these infants and produce clinical bleeding.

LONG.TERM CONSEQUENCES

Little if any data pertaining to man exist on this

question. Data derived from experimental

ani-mals are also rare. However, two reports

concern-,qing possib1e permanent sequelae of prenatally

‘administrated aspirin seem worthy of’ ‘mention.

Butcher et al.’5 investigated the learning ability

of rats exposed to subteratogenic amounts of

substances known to cause prenatal

malforma-tions of the central nervous system. Their

investi-gations indicated that postnatal learning deficits

occur following exposure to aspirin. The results

led them to conclude that aspirin, which is

teratogenic to the animal’s central nervous

system, causes psychological impairments in

offspring even when administered in amounts at

which no gross malformations are observed.

Woo and Hoar36 exposed rats to methyl

salicy-late on days 10 and 1 1 of gestation. Retarded

renal development, particularly growth of the

renal papilla, and increased number of both

transient and permanent renal abnormalities

were observed in fetuses near term. Nearly 10% of

the kidneys from treated animals showed

perma-nent gross dilation of the renal pelvis and

reduc-tion of renal parenchyma at weaning. The

remainder of the animals, however, experienced a

rapid growth of renal papillary length to normal,

so that in these animals the transitory formation

of a large pelvis resulted in an “apparent transient

hydronephrosis.”

The clinical relevance of each of these findings

in man is, at present, unknown, and will remain so

because current concepts of the ethics of human

experimentation prohibit this type of fetal

research.

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COMMENT

It must be remembered that at any time the

mother takes a medication or drug, whether

prescribed or self-administered, the fetus becomes

the unwanting and unwilling recipient.

There-fore, the risk/benefit ratio must be carefully

considered before prescribing any medications.

The maternal benefit may, in fact, outweigh the

fetal risk. On the other hand, the wholesale

administration of agents for every minor

symp-tom must be discouraged, not only as

inappro-priate, but potentially dangerous.

Although the results of the animal studies leave

little doubt that prenatal administration of aspirin

in amounts far above pharmacologic dosage is

associated with an increased incidence of

congen-ital anomalies, the clinical relevance of these

findings to man remains in question. In the

human, any relationship between the

consump-tion of aspirin during pregnancy and congenital

malformations has been found in retrospective

studies or case reports, which are indirect and

possessed with obvious shortcomings such as those

previously discussed. Unfortunately, these studies

do not unequivocally demonstrate the presence or

absence of a teratogenic effect. The answer to this

question will most likely remain unanswered

because existing legislation makes it impossible to

further study this association in the best model,

man himself.

Most of these studies did, however, show that

the taking of aspirin later in pregnancy was

associated with the presence of adverse effects in

both the mother and fetus. Birth weights of

infants of mothers who chronically ingested

aspi-rin were significantly lower, and there was an

increased incidence of stillbirths and neonatal

deaths. The length of pregnancy and labor was

prolonged, and the incidence of antepartum and

postpartum bleeding as well as other complicated

deliveries was increased.

For these reasons, the Panel on

Over-the-Counter Drugs of the U.S. Food and Drug

Admin-istration has concluded that there is a potential

hazard to the use of aspirin during pregnancy and

recommends the following warning on all

aspirin-containing products: “Do not take this product

during the last three months of pregnancy except

under the advice and supervision of a

physi-cian.”

REFERENCES

1. Carter MP: Relationship Between Antibiotic Therapy in Early Pregnancy and Congenital Malformations,

thesis. University of Oxford, Oxford, England,

1964.

2. Hill RM: Drugs ingested by pregnant women. Clin

Pharmacol mar 14:654, 1973.

3. Forfar JO, Nelson MM: Epidemiology of drugs taken by pregnant women: Drugs that may affect the fetus adversely. Gun Pharmacol Ther 14:632, 1973.

4. Collins E, Turner C: Maternal effects of regular salicy-late ingestion in pregnancy. Lancet 2:335, 1975. 5. Palmisano PA, Gassady C: Salicylate exposure in the

perinate. JAMA 209:556, 1969.

6. Levy C, Jaffe J:Relationship between dose and apparent volume of distribution of salicylate in children.

Pediatrics 54:713, 1974.

7. Levy C: Salicylate pharmacokinetics in the human neonate, in Morselli PL, Caranttini 5, Sereni F (eds): Basic and Therapeutic Aspects of Perinatal

Pharmacology. New York, Raven Press, 1975, p

319.

8. Warkany J, Takacs E: Experimental production of congenital malformations in rats by salicylate

poisoning. Am I Pathol 35:315, 1959.

9. Larsson KS, Ericksson M: Salicylate-indiiced fetal death and malformations in two mouse strains. Acta Paediatr Scand 55:569, 1966.

10. Trasler DC: Aspirin-induced cleft lip and other malfor-mations in mice. Lancet 1:606, 1965.

11. Palmer AK: Sporadic malformation in laboratory animals. Adv Exp Med Biol 27:48, 1972.

12. Wilson JG: Causes of developmental defects in man, in

Environment and Birth Defects. New York, Academic Press Inc. 1973, p 48.

13. Fritz H: Modification of teratogenicity by simultaneous-ly interfering agents, in Fourth International Conference on Birth Defects. International

Con-gress Series 297, Amsterdam, Excerpta Medica,

1973, p 90.

14. Levy CL, Amsel P, Elliott HG: Kinetics of salicyluric acid elimination in man. I Pharm Sci 58:827,

1969.

15. Beall JR. Klein MF, cited by Fed Register 42:35400, 1977.

16. Goldman AS, Yakovac WC: The enhancement of salicy-late teratogenicity by maternal immobilization in the rat. I Pharmacol Erp Titer 142:351, 1963. 17. Richards ID: A retrospective inquiry into possible

tera-togenic effects of drugs in pregnancy. Adv Exp Med

Biol 27:441, 1972.

18. Nelson MM, Forfar JO: Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. Br Med I 1:523, 1971. 19. Saxen I: Associations between oral clefts and drugs taken

during pregnancy. lnt I Epidemiol 4:37, 1975. 20. Turner C, Collins E: Fetal effects of regular salicylate

ingestion in pregnancy. Lancet 2:338, 1975. 21. Grombie DL, Pinsent K, Slater BG: Teratogenic

drugs-R.G.G.P. survey. Br Med I 4:178, 1970.

22. Slone D, Heinonen 0, Kaufman D, et al: Aspirin and congenital malformations. Lancet 1:1373, 1976.

23. Eriksson M: Salicylate induced foetal damage during late pregnancy in mice: The modifying effect of repeated administration and dosage. Acta Paediatr Scand 59:517, 1970.

24. Aiken JW: Aspirin and indomethacin prolong

parturi-tion in rats: Evidence that prostaglandins

contrib-ute to expulsion of fetus. Nature 240:21, 1972.

25. Chester R, Dukes M, Slater SR, et al: Delay of parturi-tion in the rat by anti-inflammatory agents which

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inhibit the biosynthesis of prostaglandins. Nature

240:37, 1972.

26. Waltman R, Tricomi V, Shabanah EH, at el: The effect of anti-inflammatory drugs on parturition

parame-ters in the rat.Prostaglandins 4:93, 1973.

27. Shapiro 5, Monson R, Kaufman D, et al: Perinatal

mortality and birth-weight in relation to aspirin

taken during pregnancy. Lancet 1:1375, 1976. 28. Vane JR: Inhibition of prostaglandin synthesis as a

mechanism of action for aspirin-like drugs. Nature

New Biol 231:232, 1971.

29. Tuchmann-Duplessis H, Hiss D, Mottot C, et al: Effects of prenatal administration of acetylsalicylic acid in rats. Toxicology 3:207, 1975.

30. Lewis RB, Schulman JD: Influence of acetylsalicylic acid, an inhibitor of prostaglandin synthesis, on the duration of human gestation and labour. Lancet 2:1159, 1973.

31. Gorhy DC, Schulman I: The effects of antenatal drug administration on aggregation of platelets of newborn infants. I Pediatr 79:307, 1971.

32. Bleyer WA, Breckenridge RT: Studies on the detection of adverse drug reactions in the newborn: II. The effects of prenatal aspirin on newborn hemostasis. JAMA 213:2049, 1970.

33. Haslam RH: Neonatal purpura secondary to maternal salicylisln. I Pediatr 86:563, 1975.

34. Haslaln RR, Ekert H, Gillam CL: Hemorrhage in a neonate possibly due to maternal ingestion of salic-ylate. I Pediatr 84:556, 1974.

35. Butcher RE, Vorhees CV, Kimmel CA: A learning impairment from maternal salicylate treatment in rats. Nature New Biol 236:211, 1972.

36. Woo DC, Hoar RM: Apparent hydronephrosis as a normal aspect of renal development in late gesta-tion of rats: The effects of methyl salicylate. Tera-tology 66:191, 1972.

ACKNOWLEDGMENT

The valuable assistance of Chris Montoya in the

prepara-tion of the manuscript is gratefully acknowledged.

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1978;62;930

Pediatrics

Donald G. Corby